Primary defect in CD8+ lymphocytes in the antibody deficiency disease (common variable immunodeficiency): abnormalities in intracellular production of interferon-gamma (IFN-gamma) in CD28+ ('cytotoxic') and CD28- ('suppressor') CD8+ subsets.
We have measured by flow cytometry the ability of subsets of CD8+CD3+ lymphocytes within mononuclear cell preparations to make intracellular cytokines (IL-2, tumour necrosis factor-alpha (TNF-alpha) and IFN-gamma) on stimulation in vitro with phorbol myristate acetate (PMA) and ionomycin for 16 h. These CD8+ subsets were defined by the presence or absence of CD28 or HLA-DR. Subsets of normal CD8+ cells were compared with cells from the antibody deficiency disease common variable immunodeficiency (CVID). In CVID there was a significant increase in the production of IFN-gamma in the CD8+CD28+ subset ('cytotoxic'). This reflects a shift in this disease towards an excessive Th1 response away from B cell help. Paradoxically, some CVID patients also showed a reduction in IFN-gamma production in the CD8+CD28- subset ('suppressor') which was associated with a failure of these cells to maintain a state of activation after a stimulus in vitro. The B cell problem in this disease is known to be related to a failure of T cell help shown by an inability to produce the antigen-specific CD4+ memory T cells needed for successful B cell maturation. The two pathological CD28 subsets of CD8+ cells we have found in CVID may both be detrimental to a normal CD4-dependent immune response. The CD28- suppressor subset expands and is unable to maintain activation and cytokine secretion, and the CD28+ cytotoxic subset is over-producing the Th1 cytokine IFN-gamma.
North
M E
ME
MRC Immunodeficiency Group, Department of Clincal Immunology, Royal Free Hospital School of Medicine, London, UK.
Webster
A D
AD
Farrant
J
J
D000328:Adult; D000368:Aged; D018106:CD28 Antigens / Q000276:immunology*; D016827:CD8 Antigens / Q000276:immunology*; D017074:Common Variable Immunodeficiency / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D005260:Female; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D016176:T-Lymphocyte Subsets / Q000276:immunology*
D018106:CD28 Antigens; D016827:CD8 Antigens; D016207:Cytokines; D007371:Interferon-gamma